The Entropic Brain - Revisited

Neuropharmacology xxx (2018) 1e 1 e12

Contents lists available at ScienceDirect

Neuropharmacology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m/ m/ l o c a t e / n e u r o p h a r m

Invited review

The entropic brain - revisited Robin L. Carhart-Harris Psychedelic Research Group, Neuropsychopharmacology Unit, Imperial College London, London, United Kingdom

a r t i c l e

i n f o

a b s t r a c t

Article history:

The entropic brain hypothesis proposes that within upper and lower limits, after which consciousness may be lost, the entropy of spontaneous brain activity indexes the informational richness of conscious states. Here the hypothesis is revisited four years on from its original publication. It is shown that the principle that the entropy of brain activity is elevated in the psychedelic state is increasingly well supported by separate and independent studies and analyses, and evidence for greater brain criticality under psychedelics is also highlighted. It is argued that heightened brain criticality enables the brain to be more sensitive to intrinsic and extrinsic perturbations which may translate as a heightened susceptibility to set and setting . This updated version of the original entropic brain hypothesis now offers more concrete concrete information information on speci�c measures of brain entropy and suggests new studies to scrutinise it further, as well as examine its utility for describing and informing the treatment of psychiatric and neurological conditions such as depression and disorders of consciousness. Crown Copyright © 2018 Published by Elsevier Ltd. All rights reserved.

Received 9 January 2018 Received in revised form 15 February 2018 Accepted 12 March 2018 Available online xxx Keywords:

Psychedelics Serotonin Criticality 5-HT2A Depression Entropy

“

”

“

”

Contents 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 10.

Introd Introduct uction ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 An updat update e on neuroim neuroimagi aging ng studie studiess with psyc psyched hedeli elics cs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 The functi functiona onall mean meaning ing of increased brain entropy ? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 How might might we bette betterr test the the entrop entropic ic brain brain theory? theory? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1 4.1. Speci Specific fic chall challeng enges es . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. 4.2. Propos Proposed ed soluti solutions ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Do psyche psychedel delics ics facil facilita itate te emotio emotional nal insigh insight, t, and if so, how? how? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Can psyched psychedelic elic-indu -induced ced consciou consciousness sness-enri -enrichmen chmentt be used to treat disorders disorders of consciou consciousness sness? ? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Critic Criticali ality ty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Serot Serotoni onin n and the entrop entropic ic brain brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Discus Discussio sion n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclu Conclusio sions ns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Ackno Acknowl wled edgem gement entss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Suppl Suppleme ementa ntary ry data data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Refer Referenc ences es . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 ‘

’

1. Introduction

subjective quality of any given conscious state, and speci�cally the richness of its content content,, can be index indexed ed by a quant quantita itativ tive e measur measure e of the magnitude of entropy (in the information theoretic sense) in a given parameter of spontaneous brain activity, such as oscillations in electrical potentials recorded with EEG or MEG. The hypothesis was, and is, heavily in �uenced by basic principles of information theory theory and more more speci speci�cally cally,, the notion notion that that entrop entropy y indexe indexess simultaneously both our uncertainty about the future behaviour of ‘

This review aims to revisit and update a previous theory of conscious conscious states, states, namely the entropic brain hypothesis (Carhart(CarhartHarris et al., 2014). 2014). The entropic brain proposes that the qualia or ‘

’

‘

’

E-mail address: [email protected]. [email protected] .

’

https://doi.org/10.1016/j.neuropharm.2018.03.010 0028-3908/Crown 0028-3908/Crown Copyright © 2018 Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Carhart-Harris, R.L., The entropic brain - revisited, Neuropharmacology (2018), https://doi.org/10.1016/ j.neuropharm.201 j.neuropharm.2018.03.01 8.03.010 0

Trusted by over 1 million members

Try Scribd FREE for 30 days to access over 125 million titles without ads or interruptions! Start Free Trial Cancel Anytime.







2

R.L. Carhart-Harris / Neuropharmacology xxx (2018) 1e 1 e12

a dynamic system and its information content e such that greater entropy equals greater uncertainty and information-content. Thus, maintains that uncertainty uncertainty and informationinformationthe entropic entropic brain brain maintains content content are near equivale equivalents nts and that entropic-brainentropic-brain-states states are experienced as content-rich but unpredictable and uncertain. The theory theory lends lends heavily heavily from from resear research ch with with classic psychedelic1 compounds, which have been shown to robustly and reliably increase brain entropy within the psychedelic state . The great merit of applying the measure of entropy in cognitive neuros neuroscie cience nce is that that it is uniquel uniquely y adept adept at bridgin bridging g the physica physicall and subjective divide; mere � ip sides of the same coin - but different sides nonetheless.2 Since publication of the initial entropic brain paper in 2014 (Carhart-Harris (Carhart-Harris et al., 2014), 2014 ), a number of new functional tional brain brain imagin imaging g studies studies with with psyche psychedel delics ics have have been been publish published ed (Alonso et al., 2015; 2015; Atasoy et al., 2017; 2017; Barrett et al., 2017; 2017 ; Bouso et al., 2015 2015; Carhart-Ha Carhart-Harris rris et al., 201 2016b 6b,, 2017c; 2017c; Kaelen Kaelen et al., 2016;; Kraehenmann et al., 2015 , 2016 2016 2016;; Lebedev et al., 2015, 2015 , 2016 2016;; Mueller et al., 2017; 2017; Muller et al., 2017; 2017; Palhano-Fontes et al., 2015; 2015 ; Petri et al., 2014; 2014; Preller et al., 2016, 2016 , 2017 2017;; Roseman et al., 2014, 2014 , 2016,, 2017 2016 2017;; Sampedro et al., 2017; 2017 ; Sanches et al., 2016; 2016 ; Schartner et al., 2017; 2017; Schenberg et al., 2015; 2015 ; Schmidt et al., 2017; 2017 ; Speth et al., 2016; 2016; Tagliazucchi et al., 2014, 2014 , 2016b; 2016b; Timmermann et al., 2017;; Valle et al., 2016a; 2017 2016a; Viol et al., 2017). 2017). These, plus time, re �ection, and the publication of new imaging studies on other altered states e.g. (Schartner (Schartner et al., 2015) 2015 ) plus new research on serotonin functio function n (e.g. (e.g. (Matias et al., 2017 2017), have motivated motivated the present present revision. Key Key compon component entss of this this revisi revision on include include:: 1) a more more explic explicit it statement that the qualia of time-averaged conscious states can be predicted by brain entropy, 2) reference to speci �c measures of entropy entropy thought to meaningfully meaningfully index the qualia of conscious conscious states, 3) a speci�c example example of an important important empirical, empirical, therapeutherapeutically relevant question that may be tackled by the hypothesis, 4) a speci�c example of a clinical problem (namely disorders of consciousness) where the hypothesis may inspire a novel intervention, 5) new data and thoughts on properties of brain criticality in the psyche psychedel delic ic state, state, 6) how height heightene ened d brain brain critical criticality ity confer conferss maximal sensitivity to perturbation via intrinsic or extrinsic sources ces ( set and setting), setting), 7) 7) how there there may may be an upper bound to the entropic entropic brain principle principle beyond beyond which unconsciousness unconsciousness occurs (Fig. 1), 1), and 8) how recent �ndings on brain serotonin encoding behavioural responses to uncertainty mesh well with the entropic brain hypothesis. ‘

‘

“

”

’

’

“

2. An update on neuroimagi neuroimaging ng studies with psychedelics psychedelics

Accor Accordi ding ng to a PubMe PubMed d sear search ch at the the time time of subm submis issio sion n (January 2018), since the 2014 publication of the original entropic brain paper, there have been over 30 new empirical neuroimaging papers papers publish published ed on the effect effectss of psyche psychedeli delics cs on the human human brain. brain. Since there are relatively few human neuroimaging teams working with these compounds, it is relatively easy to locate where these

1

Classic psychedelics are perhaps best de �ned pharmacologically as drugs that have direct agonist properties properties at the serotonin 2A receptor receptor sub-type ( Nichols, 2016). 2016).

have come from, namely: Spain (Alonso ( Alonso et al., 2015; 2015; Bouso et al., 2015;; McKenna and Riba, 2017; 2015 2017 ; Sanches et al., 2016; 2016 ; Valle et al., 2016b), 2016b ), Switze Switzerla rland nd (Bar Barret rettt et al., 20 201 17; Kraehen Kraehenmann mann et al., 2015,, 2016 2015 2016;; Mueller et al., 2017; 2017 ; Muller et al., 2017; 2017 ; Preller et al., 2016,, 2017; 2016 2017; Schmidt Schmidt et al., 201 2017 7), Brazil (Palhano (Palhano-Font -Fontes es et al., 2015;; Schenberg et al., 2015; 2015 2015 ; Viol et al., 2017), 2017 ), and the UK (Atasoy ( Atasoy et al., 20 201 17; Carhart-Ha Carhart-Harris rris et al., 201 2016b 6b,, 2017c; 2017c; Kaelen Kaelen et al., 2016;; Lebedev et al., 2015, 2016 2015 , 2016 2016;; Petri et al., 2014; 2014 ; Roseman et al., 2014,, 2016, 2014 2016, 2017; 2017; Schartn Schartner er et al. al.,, 20 201 17; Speth Speth et al al.,., 20 201 16; Tagliazucchi et al., 2016b; 2016b; Timmermann et al., 2017). 2017 ). One aspect of the present task is to digest these recent contributions and summarise what they have added to our understanding of the human brain effects of psychedelics. Given the focus of the present paper, this this will will be done with with speci speci�c refer referenc ence e to the entrop entropic ic brain brain hypothesis. The � rst thing to note is that the theory has received signi �cant empiri empirical cal support support since since its introd introducti uction on in 2014 2014 (Ata Atasoy soy et al. al.,, 20 201 17; Lebedev Lebed ev et al., 2016; 2016; Schartner et al., 2017 2017; Tagliazucchi et al., 201 2014 4; Violl et al Vio al.,., 20 201 17). For examp example, le, analys analyses es of Lempel Lempel-Zi -Ziv v comple complexit xity y or entropy (in the extended sense) in MEG-measured spontaneous brain activity under a range of psychedelic (i.e. LSD and psilocybin) and psychedelic-l psychedelic-like ike (i.e. ketamine) ketamine) drugs revealed revealed consistently consistently increased brain entropy in the psychedelic state (Schartner (Schartner et al., 2017). 2017 ). Moreov Moreover er,, the magnit magnitude ude of these these increas increases es in entrop entropy y corre correla late ted d with with the the subje subject ctiv ive e inte intensi nsity ty of the the drug drug trips (Schartner et al., 201 2017 7). It was also found that fMRI-measured brain entropy was elevated acutely under LSD and that the magnitude of this, predicted subsequent changes in personality two weeks later (Lebedev et al., 2016). 2016 ). In terms of outside replication, a separate team recently recently reported reported increased increased fMRI-measur fMRI-measured ed brain entropy entropy under a psychedelic, in this case, with the DMT-containing drink, ayahuasca (Viol (Viol et al., 2017); 2017); moreover, an especially recent study by my group recorded increased brain entropy under intravenous DMT, using EEG and the Lempel-Ziv measure ( Timmermann et al., 2018). 2018 ). Another notable recent contribution relates to the novel application of connectome harmonics to the psychedelic state ( Atasoy et al al.,., 20 201 17). Consist Consistent ent with with the entrop entropic ic brain brain hypot hypothes hesis is (Carhart-Harris et al., 2014), 2014 ), as well as previous analyses with fMRI and psilocybin (Tagliazucchi (Tagliazucchi et al., 201 2014 4), this approach revealed an expan expanded ded repert repertoir oire e of brain brain states states under under LSD, and again, again, this this effect effect correlated with the intensity of the subjective experience ( Atasoy et al., 2017). 2017). To our knowledge, this is the �rst time that a property of brain criticality under a psychedelic has been clearly and intent intention ionally ally measur measured ed (here (here the power power law distrib distributio ution n of conne connect ctom omee-ha harm rmon onic ic brai brain n state states) s) and and the the resul results ts were were intriguing, with an apparent enhancement of criticality under LSD relative to the normal waking state ( Atasoy et al., 2017). 2017). As with ndings of increa increased sed brain brain entrop entropy y under under psyche psychedel delics ics (e.g. (e.g. �ndings Schartner et al., 2017), 2017 ), increased brain criticality relative to normal waking consciousness (or indeed any other state of consciousness) is an anomaly in the scienti �c literature (Atasoy (Atasoy et al., 2017), 2017), and may there therefor fore e speak speak to the excep exception tionaln alness ess of the psyche psychedel delic ic state, state, something that is widely recognised by those who have experienced their remarkable subjective effects ( Huxley, 1959) 1959) - but not so much much by the broade broaderr cognitiv cognitive e neuros neuroscien cience ce commun community ity.. It would be encouraging to think that these novel neurobiological ‘

’







R.L. Carhart-Harris / Neuropharmacology xxx (2018) 1e 1e12

3

Fig. 1. 1. The entropic brain. brain. Consciousness is proposed to arise within a critical zone at which the entropy or complexity of brain activity is neither too ordered nor disordered. Normal waking consciousness is proposed to inhabit a band within this zone, albeit towards its upper end. Psychedelic compounds are proposed to shift brain entropy and conscious content upwards, higher within the zone of criticality, towards greater conscious content, � exibility exibility of mind and emotiona emotionall lability lability but with a trade-off trade-off on the preservation of assumptions or beliefs and the sense of familiarity and assuredness they confer. Brain entropy (and criticality) may reach an upper limit at which consciousness is effectively lost - perhaps because phenomenal experience cannot be preserved beyond this point and thus, remembered. Sedatives and anaesthetics shift the brain downwards, i.e. into a subcritical zone and eventual unconsciousness, through loss of content and phenomenal experience. N.B. This �gure is intended to be a working schematic; no hard claims claims are made about the relative scale or dimensions of each domain.

3. The functiona functionall meaning of increased brain entropy ? ‘

’

the process of decoding, i.e. that a decoder decoder be able to make sense of the potentially rich information content of a complex, unpredictable phenomenon (Gleick, (Gleick, 2011). 2011). As with uncertainty , reference ence to entr entrop opy y as information (Shannon, 1949 1949), ), has has led led to charg charges es of anthropomorphism (Gleick, (Gleick, 2011). 2011). In this context, a key challenge for the entropic brain hypothesis is to decipher the complex code instantiated by brain activity in order to may make more speci�c and compelling compelling mappings mappings to the feeling feeling states states they encode. encode. ‘

The �rst thing to note is that there is strong evidence that the entropy of spontaneous brain activity is reduced during states of reduced consciousness (Olofse (Olofsen n et al., 2008 2008;; Schartner et al., 2015; 2015 ; Zhang et al., 2001; 2001 ; Burioka et al., 2005) 2005) and that entropy measures can be used to accurately accurately distinguish distinguish between between waking consciousness, loss of consciousness and even the minimally conscious state (Casali et al., 2013; 2013; Schartner et al. , 2015; 2015; Zhang et al., 2001). 2001 ). In this context, the discovery of a state in which brain entropy is elevated above above its alrea already dy high high level level at normal normal wakin waking g consciou consciousne sness ss is truly truly noteworthy noteworthy (Schartner et al., 2017). 2017 ). If entropy indexes the level of consciousness , does it not follow that higher entropy in the psychedelic state relates to an increase in some quality of consciousness above its (already high) level during the normal awake state? It is important not to romanticise the psychedelic experience here, with mystical-s mystical-sounding ounding notions of expanded-consciousness , but equally, one should not be shy of the result nor its functional implications. Accordingly, it seems entirely reasonable to infer that there is an expansion in some key property of consciousness under psychedelics, while another may be compromised, e.g. analytical and convergent thinking (Carte ( Carterr et al., 2005; 2005 ; Kuypers et al., 2016). 2016 ). It is proposed here that, to a critical point, beyond which the ability to preserve phenomenal experience and thus consciously re�ect on it may be entirely entirely lost, lost, the property property of consciousness consciousness that is most reliably indexed by brain entropy and enhanced under psyche psychedel delics ics is its richness. Othe Otherr term termss that that could could refe referr to the the same same property might be: content , complexity and information . These largely interchangeable terms harmonise well with the nomen‘

‘

‘

’

’

’

4. How might might we better test the entropic entropic brain theory? 4.1. 4.1. Speci �c �c challenges

’

‘

‘

’

‘

’

’

‘

’

Improving our mappings between spontaneous brain and mind phenomena is a major scienti �c challenge. Doing so will enable us to better characterise and predict properties of different conscious states, and where appropriate, treat psychiatric and neurological disorders. disorders. Since it is the spontaneous spontaneous brain activity activity underlying underlying conscious states about which we are most interested, our techniques niques for realising realising this mapping will bene�t most from retaining an intimacy to the original phenomena of interest. By implication, the study of stimulus-evoked transients, including discrete perturbat turbations ions - such as brain brain stimul stimulati ation on (Casa Casali li et al. al.,, 20 201 13; Massimini et al., 2009) 2009) or responses within speci �c behavioural paradigms, mayhave relati relativel vely y limite limited d explan explanato atory ry potent potential ial due to their their being being detached from the central phenomena of interest, i.e. spontaneous states - naturally naturally unfolding unfolding across time. In contrast, contrast, improvin improving g our methods of sampling spontaneous mind and brain states in situ may yield more relevant insights. ‘

’







4


uncertainty principle , and it is not an easy problem to resolve. ’

( Gleick, 2011) 2011) Nature is sensitive to our experiments. (Gleick,

“

”

hypot hypothes hesis, is, it may be especial especially ly constr constructi uctive ve to offer offer a speci speci�c example here of a particular problem felt to be deserving of special attention and about which a potential solution may be proposed. Thankfully, the true origin and meaning of neologism psychedelic is becoming increasingly well recognised and understood. It dates back to the mid 1950s and an exchange between two Brits (one, the famous author - Aldous Huxley) in which they sought to ( Huxley et al., �nd a more appropriate term for these compounds (Huxley 1977). 1977 ). The objective was to devise a word that would better capture their core psychological properties than the relatively shallow and arguably misleading alternative hallucinogen . It was Huxley's interlocute interlocuter, r, the psychiatrist psychiatrist and psychedelic psychedelic research research pioneer pioneer Humphr Humphrey ey Osmond Osmond who would coin the term term psychedelic combining two ancient Greek words for mind or soul ( psyche, reveal or make make manifest manifest or visible (delein, dhlεin) Jycή ) and to reveal to lay princi principal pal emphas emphasis is on these these compoun compounds' ds' mind-revealing effects. The notion that a principal property of psychedelics is their ability to reveal aspects of the mind that are normally not fully visible, was (Cohen,1964 (Cohen,1964;; Grof, 1979 979;; Sandison, 1954 954), ), and remains (Carha Carhart-Ha rt-Harris rris and Frist Friston, on, 201 2010 0; Kraehe Kraehenmann nmann et al., 201 2017a,b 7a,b;; Richards, 2015), 2015), widely accepted among those most familiar with their effects, if through direct personal experience, or second or third-hand observation. Remarkably however, that psychedelics do this, remains a mere assumption/hypothesis that has never been systematically measured and tested, and therefore given an opportunity to be veri �ed or falsi�ed. It seems reasonable to begin by acknowledging that this relative tively ly majo majorr over oversig sight ht may may be expla explain inab able le - if not not excus excusab able le - by the the unreasonable dif �culty of conducting human research with psychedelics 3 (Nutt et al., 2013), 2013 ), let alone testing such an abstract and paradigm-challenging idea . 4 Tackling this problem pragmatically however, we may begin by deconstructing it into simpler, more concrete and testable components. One such component is that psychedelics psychedelics facilitate facilitate emotional emotional insight insight , i.e. de�nabl nable e as the the acquisition of new thoughts, ideas or realisations about one's self (or persona - to use a Jungian term), assumptions and behaviour. Such insights may (or may not) then lead to subsequent changes in assumptions, perspectives and behaviour. We may operationally de�ne emotional insight using a revised version of a scale previously devised and employed to test the notion that dreams facilitate emotional insight (Edwards ( Edwards et al., 2013) 2013 ) . 5 This measure could be employed within a placebo-controlled study with a psychedelic, with the hypothesis that scores would be signi �cantly higher in relation to the psychedelic experience than with placebo. Moreover, to add speci �city and thus, potential potential strength strength to subsequent subsequent inferences, inferences, a psychoactive psychoactive control control drug could be introduced, introduced, such as a benzodiazepi benzodiazepine, ne, stimulant stimulant or non-psychede non-psychedelic lic dissociative. dissociative. Interestingly, a recent study largely adhered to such a design and found found greate greaterr report reported ed psychol psychologi ogical cal insight insight in relat relation ion to the psychedelic psychedelic (psilocybin) (psilocybin) experience experience than with experience experiencess produced by an active active control control (dextrom (dextromethorp ethorphan) han) (Carbonaro ( Carbonaro et al., ‘

Moreover, in the context of psychedelic research, it has proved apparen apparentt thatinstructin thatinstructing g participa participantsto ntsto engagein engagein certain certain behaviou behaviours rs or withcertain withcertain stimuli stimuli tends tends to suppres suppresss theintensityof theintensityof thebasal, ongoing psychedelic state. Another issue is that interpretations of results based on controlled experimental perturbations should carry important caveats e and these are not always stated. More specificall ically, y, likel likely y due to a gener generali alised sed inabil inability ity to engag engage e with with stimul stimulii that that are relatively unengaging and/or dif �cult to focus on when in the throes throes of an intrinsi intrinsicall cally y stimulat stimulating ing psychede psychedelic lic trip , it is typi typica call for for such experim experiments ents to yield yield (arguabl (arguably y uninter uninteresti esting) ng) negativ negative e �ndings -e.g.see(Muthukumar -e.g.see(Muthukumaraswam aswamy y et al., 201 2013 3; Timm Timmerm ermann ann et al., 20 201 17) for relevan relevantt discussions. discussions. Similar Similar critiqu critiques es have have been been made of �ndings of impaired cognition and brain responsiveness responsiveness in pathological conditions such as schizophrenia and/or major depressive disorder e since the most plausible (but less exciting) interpretation of such negative �nding ndingss is that that the patie patient nt is simpl simply y less less able able and/orwilli and/orwilling ng to engage with tasks and stimuli in question, and thus, the impairment(s) are generalised rather than speci�c. Caution Caution is therefor therefore e advised when choosing to employ conventional behavioural paradigms in the context of acute administration studies with psychedelics, delics, as this may encourag encourage e speci speci�c inference inferencess to be made on what are in actuality, actuality, non-speci�c negative outcomes. ‘

’

‘

’

4.2. Proposed Proposed solutions solutions

In the mid 1990s 990s cogniti cognitive ve neuros neuroscie cienti ntist st Franci Francisco sco Varela Varela conceded that no simple theoretical �x or missing ingredient ingredient could could magica magically lly bridge bridge the ontolo ontologica gicall divide divide betwee between n brain/ brain/ object objective ive and mind/s mind/subje ubjecti ctive ve phenom phenomena ena (Varel Varela, a, 199 1996 6). In conceding this simple but essential point, he was then able to promote a pragmatic approach to the problem. He proposed that it is still very much possible to make meaningful mappings between irreducible mind-stuff and intimately intimately associated brain-stuff such that translations translations between between them become relatively relatively seamless, and differ differenc ences, es, unobvi unobvious. ous. In making making this this point, point, Varela Varela cited cited Edmund Edmund Husser Husserl's l's notion notion of fundamental fundamental correlation correlation and and he named his approach neurophenomenology (Varela, ( Varela, 1996). 1996). The pragmatism of neurophenomenology neurophenomenology chimes well with that of the entropic brain. However, it is recognised that signi �cant improvement mentss must must be made made in our our samp sampli ling ng of both both brai brain n and and mind mind,, if mor more compelli compelling ng and speci speci�c fundamental discovere red. d. fundamental correlatio correlations ns are to be discove Moving beyond the supportive � ndings that have already been cited (Atasoy et al., 2017; 2017; Lebedev Lebedev et al., 20 201 16; Schartner Schartner et al., 201 2017 7; Tagliazucc Tag liazucchi hi et al., 201 2014 4; Violet al.,201 al.,2017 7),asigni�cantadvancement cantadvancement for the entropic brain will be to go beyond the general but important statement that entropy is a (perhaps uniquely) powerful mind-brain bridge, to highlight speci�c cases where it bridges in a way that othe otherr measu measure ress do not. not. To help help with with this,it this,it is encou encoura ragin ging g to note note that that signi�cant cant progre progress ss is being being made in functio functional nal neuro neuroimag imaging ing to develop more dynamically sensitive measures, such as sliding windows dows (Na Naka kaii et al al.,., 200 2006 6), point-pr point-proce ocess ss (Ta Taglia gliazucc zucchi hi et al., 20 2012 12)) and and intrinsic intrinsic ignition ignition (Deco et al., 2017; 2017; Deco and Kringelbach, 2017) 2017 ) analy and with with ard subj ive ien plin ‘

‘

’

‘

’

‘

‘

‘

’

’

’

’

’

‘

’

‘

‘

‘

’

’

‘

‘

‘

’

’

‘

’

’



’

’

3 The reasons for this are manifold but can perhaps most simply and accurately be traced to stigma and related conservatism affecting key decision makers within








2017). 2017). If further further positive positive �ndings were to be obtained, key questions would then ensue, such as: what underlies such emotional insight (e.g. in terms of brain activity), and are such events amenable to captur capture e and measur measureme ement nt in realreal-tim time, e, i.e. i.e. as they they arise, arise, as opposed opposed to merely in retrospect? If the insight arises as a discrete event or epoch in time, then it stands to reason that it is amenable to capture ture,, butif it is prot protra ract cted ed,, even even tothe exte extent nt that that it crys crysta talli llise sess after after the psychedelic trip has ended, then capturing and measuring this seems less feasible. In the interests of pragmatism (and plausibility), ity), let us imagin imagine e that that the entropic entropic beginn beginning ingss of emotio emotional nal insight, do occur in discernable epochs under psychedelics. If we accept accept this this possibil possibility ity,, how then then might might we capture capture such epochs epochs and assess their relationship to insight? Button-press to signify the occurrence of discrete spontaneous events is an approach that has been used in the past, e.g. in relation to auditory hallucinations hallucinations in psychosis psychosis (Lero Leroy y et al., 2017 2017) and spontaneously spontaneously arising thoughts (Ellamil et al.,2016) al.,2016) but the overhangin hanging g psycho psychologi logical cal in�uenc uence e of the the inst instru ruct ction ion to butto button n press, as well as the subsequent motor actions, associated artefacts and the preceding deliberation on and intention to act, may suppress press and/or and/or confoun confound d the target target phenom phenomeno enon n and theref therefor ore e create create false and/or unreliable attributions. Thus, an alternative to button press may be needed and one such example may be experience sampling , i.e. the procedure of cueing participants to report on the content of their recent conscious experience at random or pseudorandom time intervals (Christ ( Christoff off et al., 2009). 2009). Such reports may be brief brief and constr constrain ained, ed, e.g. e.g. delive delivered red in the form form of simple simple rating ratings, s, or more open, e.g. delivered through free speech. Due to the importance tance of brevi brevity ty and desire desire not to interf interfere ere with the naturall naturally y unfolding experience, simple ratings may be the most practical option, option, particularly particularly if concomitant concomitant functional functional neuroimagin neuroimaging g recordings are being made e which are time sensitive and expensive (e.g. especially especially with with fMRI). fMRI). Thus, a simple brief rating rating of strength strength of emotion and/or richness richness of conscious conscious experience experience could be used which which could could be supple suppleme ment nted ed postpost-hoc hoc by deta detaile iled d micr microophenomenology interviews (Petitmengin, ( Petitmengin, 201 2017 7) that seek to evoke the original feeling and probe its nature with strategic questioning. Import Important antly ly,, we might might impro improve ve on this this entire entire approa approach ch by twinning the psychedelic experience with conditions known to be especially amenable to emotional arousal and insight. As already touched touched upon, this is especially especially pertinent pertinent in the context of neuroimaging, and particularly fMRI, where due to expense, as well as mechanical and comfort-related issues, individual scans typically last for approximat approximately ely 5 e15 min, and complete scanning sessions sessions cover a period of approximat approximately ely 60 min. Thus, introducing conditions in which emotional arousal and insight can be more easily coaxed, would serve a valuable function. This could be done ef �ciently with music, structured in such a way that one may predict a priori, where intense experience and related insight may be most likely to occur. Experience sampling could track emotional strength/richness of experience in real-time and cues to rate/report on this could be suf �ciently interspersed in time, so as to minimise interfering with the natural experience itself while being suf �ciently ciently regular regular to capture capture the desired events (e.g. a simple rating every 90 e150 150 s). Although unconventional, unconventional, if using fMRI for example, one might dedicate an entire scanning ‘

’

‘

’

‘ ‘

’

‘

’

5

density EEG might be more effective modalities. A critical reader may ask, why such concern for the subjective measures, especially in a paper concerned primarily with a theory on brain function? The simple response response to this is that questions questions of how experience is sampled should be given equivalent weight to questions of how concomitant brain activity is recorded, as the aim is to optimize the strength of our correlations between the two (Petitmengin, 2017). 2017). By implication, improving the �delity of our subjective subjective measure measuress will serve this agenda agenda as effectively effectively as utilising the most powerful neuroimaging technologies and analyses. How might we tie-in the entropic brain theory to this hypothetical study and its outcomes, and what predictions would we make make about about the magnitud magnitude e of brain brain entrop entropy y during during periods periods of intensi�ed experience in which subsequent insight is reported? The The clue clue may may be in how how the the ques questi tion on has has been been fram framed ed,, i.e. i.e. that that ther there e is a temp tempor oral al sequ sequen ence ce to even events ts - with with an incr increa ease se in brainentr brainentrop opy y coinciding with a period of intense immersion and information download (which also feels unpredictable, openly explorative and experientially rich ) followed by a subsequent period of normalisation of or reduction in brain entropy, that relates to a process of integrating , decoding or sorting this information - and its subsequent sequent crystallisatio crystallisation n as insight . Mechanisms and measures of 1997 7). self-organisation may be relevant in this context ( Bak, 199 In partial support of these ideas, we have previously found that acute entropy under a psychedelic predicts sub-acute and potentially long-term changes in personality (i.e. increases in the personality trait openness to experience) (Lebedev ( Lebedev et al., 2016), 2016 ), and certain qualities of brain activity (i.e. functional connectivity) have been found to change in an opposite direction after a psychedelic exper experien ience ce than than during during it ( Carh Carhart-Ha art-Harris rris et al., 201 2017c 7c). ). These These mechanisms might be likened to those discussed in relation to the creative process (Lubart, (Lubart, 2001), 2001), in which an experience experience of insight is preceded preceded by planning planning (intention), (intention), free-associat free-association-li ion-like ke brainstorming and a subseq subsequen uent, t, delay delayed ed proces processs of evaluat evaluation ion or veri�cation (integration). Loosely, these mechanisms might also be related to the phenomena of divergent versus convergent thinking (Guilford, 1967; 1967; Kuypers et al., 2016) 2016 ) as well as exploratory versus exploitative search (Cohen (Cohen et al., 2007), 2007), in which there is an initial entropic state that is exploratory and divergent in nature which is then followed by more protracted processes of cognitive convergence and exploitation . Before Before concluding this section, section, it is worth considering a couple of addition additional al novel novel analyt analytical ical approach approaches, es, i.e. i.e. in additio addition n to applyi applying ng informa informatio tion n theore theoretic tic measur measures es of entrop entropy y to brain brain data, data, it may be possible to measure the entropy of subjective experience itself, e.g. through the richness of the language used to describe it and in properties such as the rarity of the adjectives and phrases used and contingencies between words, phrases and categories or them themes es.. Effor Efforts ts are are curr curren entl tly y bein being g made made to explo explore re how how this this canbe done done in a usefu usefull and and mean meanin ingf gful ul way way - but but serv servin ing g as inspi inspira rati tion on are are the impressive developments in natural speech analytics that have been made in psychiatry and psychopharmacology in recent years (Bedi et al., 2014, 2014, 2015). 2015). Relatedly, one may also apply validated measures of cognitive bizarreness to accounts of the psychedelic experience, as has been done recently (Kraehenmann ( Kraehenmann et al., 2017). 2017 ). Both brain and free-speech data might also be combined with machine learning methodologies with the aim of predicting new ‘

’

‘

‘

’

‘

’

’

‘

‘

’

’

‘

’

‘

’







6


6. Can psychedelic-induced psychedelic-induced consciousness-enrichment consciousness-enrichment be used to treat disorders of consciousness?

Beyond what has just been discussed, let us consider another speci�c example of an area in which the entropic entropic brain theory theory may be effect effective ively ly applied applied.. Brain Brain entrop entropy y or complexity has been found to reliably index conscious level in healthy people during normal waking waking consciousness consciousness versus the anaesthetise anaesthetised d state, state, as well as in disorders of consciousness (Casali (Casali et al., 2013; 2013; Olofsen et al., 2008; 2008 ; Schart Sch artner ner et al. al.,, 20 201 15; Zhang Zhang et al al.,., 200 2001 1). Perhap Perhapss the most impressive research in this regard has been performed by Casali et al. (2013) who (2013) who used transcranial magnetic stimulation (TMS) to pertur perturb b the brain brain in health healthy y individ individual ualss and patien patients ts with with disorde disorders rs of consciousness of varying degrees of severity. The Lempel-Ziv measure was then applied to EEG recordings of TMS-pulsed brain activity to yield the so-called perturbational-complexity index or PCI; for detailed explanations of Lempel-Ziv measures of brain activity, see (Schar ( Schartner tner et al., 201 2015 5; Zhang et al., 2001). 2001 ). This PCI approach approach was remarkably remarkably reliable reliable at differentiat differentiating ing between between disorders of consciousness, e.g. with vegetative state patients scoring lowest, followed by patients in the minimal conscious state, the emerging emerging from minimally conscious state and �nally, locked-in syndrom syndrome e and health healthy y contro controls ls during during normal normal wakefu wakefulne lness ss (Casali et al., 2013). 2013). An even more recent study showed that the same Lempel-Ziv Lempel-Ziv measure measure applied to spontaneous spontaneous (i.e. restingrestingstate, non-TMS perturbed) brain activity effectively differentiated between between consciousness consciousness and unconsciousness unconsciousness in healthy healthy individuals individuals (Schartner et al., 2015), 2015 ), and in a separate earlier study, the same basic measure was found to index depth of anaesthesia with an almost 100% sensitivity and speci�city (Zhang (Zhang et al., 2001). 2001). To our knowledge, until recently, it was generally thought that normal waking consciousness represents the (conscious) state of maxima maximall brain brain entrop entropy, y, since since all compari comparison son states states charac character terisedby isedby a relat relative ive loss of conscio consciousn usness, ess, suchas sleep, sleep, theanaesthet theanaesthetise ised d and sedate sedated d states states and disorde disorders rs of conscio consciousn usness, ess, featur feature e a correcorrespond sponding ing redu reduct ctio ion n in brain brain entr entrop opy y (Bu Buri riok oka a et al al., ., 20 2005 05;; Schartner et al., 2015). 2015). It was a remarkable discovery therefore that the psychedelic state bucks this trend, with robust increases in brain entropy exceeding the levels associated with normal waking consciousness consciousness observed observed with different different psychedelic psychedelic compounds compounds (Schartner et al., 2017). 2017 ). In addition to questions about what we are to make about these �ndings, are questions about what we are to do with them? Interventions for disorders of consciousness are relatively ineffective and/or unreliable and range from the pharmacological to surgical (Giacino et al., 2014). 2014). If reductions in consciousness relate to reductions in brain entropy (Schartner ( Schartner et al., 2015), 2015 ), and psychedelics robustly and reliably increase brain entropy (Schartner et al ., 2017), 2017), then does it not follow that psychedelics may be used to elevate conscious content in patients with disorders of consciousness? Pragmatics and need, rather than cynical conservatism, should dictate how we proceed with this idea. One logical place to start might be with non-human animal research where the hypothesis hypothesis that psychedelics lift entropy and thus, conscious content, from a sedated baseline may be tested. However, since it is dif �cult to assess assess consciou consciouss contentin contentin non-hu non-human man animal animals, s, and anaest anaesthes hesia ia to assi with with din found found int ions logical logical ‘

’

association between the phenomenology of the psychedelic state and the dream state (Kraehenmann ( Kraehenmann et al., 2017; 2017 ; Tagliazucchi and Sanz, 2018) 2018) e see also (Carhart-Harris, (Carhart-Harris, 2007; 2007; Carhart-Harris and Nutt, 201 2014 4). If these proof-of-principle experiments were to yield positive results, we might then consider taking the intervention to patients with with disor disorde ders rs of consc consciou iousne sness. ss. The The norma normall proce procedu dure re for for informe informed d consen consentt in such patients patients would would apply, apply, and given given the positive positive safety pro pro�le of psychedelics psychedelics,, and association association with positive positive mental mental health health outcom outcomes es (Carha Carhart-Ha rt-Harris rris and Goodwi Goodwin, n, 201 2017 7), albeit albeit with important caveats related to context of use ( Carhart-Harris et al., 2018), 2018), a logical and ethical case could be made in favour of conducting such a study. Again, if positive results were to be found, considerations may then turn to how the intervention could be given in a more manageable way, e.g. via adherence to a microdosing protocol protocol (Fadiman, 201 2017 7), where where threshold threshold perceptible perceptible doses of psychedelics are given 2e3 times per week to (putatively) modulate improvements in mood and cognition. Moreover, where there is suf �cient residual consciousness for this to be appropriate, such a dosing regimen regimen might also be combined with conventional conventional rehabilitation therapy. ‘

’

7. Criticality Criticality

It was an original hypothesis hypothesis of the initial entropic brain paper (Carhart-Harris et al., 2014) 2014 ) that psychedelics tune the brain even closer to criticality criticality6 than than is eviden evidentt in normal normal wakin waking g consciou consciousne sness ss and importantly, recent �ndings with fMRI and LSD do seem to support support this idea (Atasoy et al., 2017 2017). That That the brain exhibits exhibits characteristics of criticality is now well established (Hahn ( Hahn et al., 2012;; Fregnac, 2012 Fregnac, 201 2017 7; Tagliazucchi, Tagliazucchi, 201 2017 7; Tagli Tagliazu azucchi cchi et al., 2016a), 2016a ), and there is some evidence to suggest that the brain ordinarily resides towards the sub-critical end of a general zone of criticality (Priesemann et al., 2014), 2014 ), i.e. brain criticality may be better thought of as zone than a discrete critical point (Moretti ( Moretti and Munoz, 2013) 2013) and the waking brain seems to be positioned closer to extreme order or sub-criticality within this zone than extreme extreme disorder disorder or super super-criti -criticali cality ty (At Atas asoy oy et al al., ., 20 201 17; Priesemann et al., 2013, 2013 , 2014 2014). ). Brain dynamics have been shown to shift shift toward towardss sub-cri sub-critica ticalit lity y with with increas increasing ing cognit cognitive ive load (Fa Fager gerholm holm et al., 20 201 15) and into into super super-critic -criticalit ality y in epilep epileptic tic seizure (Meisel (Meisel et al., 2012). 2012 ). As with entropy, cases of enhanced criticality above the already high level associated with the normal waking brain are relatively unheard of in the scienti �c literature; thus, by implication, implication, increased criticality under psychedelics psychedelics is exceptional (Atasoy (Atasoy et al., 2017). 2017). What then are we to make of this? Criticality is known to confer functional advantages to a system in terms of maximising the capacity and ef �ciency of information processing through optimizing adaptability while preserving order (Shew ( Shew and Plenz, 2013), 2013), and it stands to reason that a system moving closer to criticality and/or shifting closer to the super-critical end of a critical zone is likely to favour � exibility and susceptibility to perturbation over preservation e as well as exploration over exploitation (Cohen ( Cohen et al., 2007). 2007). Re�ecting on some of the recent �ndings with psychedelics, this principle principle makes sense: for example, example, psychological psychologically ly supported supported ‘

’

‘

‘

‘

’

’

’

‘

’










(Moreno et al., 2006), 2006), and depression depression (Carhart-Harris (Carhart-Harris et al., 2016a, 2016a , 2017a;; Sanches et al., 2016). 2017a 2016 ). Moreover, several of these conditions have have been been associat associated ed with with brain brain sub-cri sub-critica ticalit lity y (Carhart-Harris et al al.,., 20 201 14) e particula particularly rly depres depression sion (Pe Peza zard rd et al. al.,, 199 996 6; Thomasson and Pezard, Pezard, 1999 1999;; Thomasson et al., 2000, 2000 , 2002 2002;; Zhang et al., 2001; 2001; Akdemir Akar et al., 2015) 2015 ) e although contradictory evidence evidence (e.g. Mende ndezz et al. al.,, 20 2012 12;; Akdemir Akdemir Akar et al., 2015 2015 ) suggests suggests that the relationship relationship between between entropy entropy and depression depression maybe be subtype and state speci �c (e.g. see Akdemir see Akdemir Akar et al., 2015 and Zhang et al., 2001), 2001), as well as sensitive to medication status (M (Mendez et al., 2012). 2012 ). Regar Regardin ding g the dynamics dynamics of mood mood itself, itself, it is intrig intriguin uing g to enter entertain tain the thought thought that, that, within within certai certain n bounds, bounds, the super super-critic -critical al end of the zone of critica criticalit lity y may favour favour positive positive mood - and perhaps even be a fundamental property of it (Carhart-Harris ( Carhart-Harris and Nutt, 2017; 2017; Thomasson et al., 2000, 2000 , 2002 2002), ), although there may be a tipping point, where the hyper- �exible (instable) individual may become become vulnerable vulnerable to a mania-rela mania-related ted condition exhibiting exhibiting behaviours such as agitation, inappropriate elation and grandiosity. It is noteworthy that such symptoms can sometimes be seen acutely and even sub-acutely with psychedelics (e.g. see https://erowid. org/experiences/), org/experiences/ ), perhaps most commonly when the experience has been been poorly poorly integr integrate ated d (Carha Carhart-Ha rt-Harris rris et al., 201 2017b 7b). ). The The noti notion on of spiritual spiritual bypassing bypassing may be relev relevant ant here, in which which transtranspersonal and/or spiritual notions and ideals are (unconsciously) used to distract ourselves from and thus avoid directly working on painful personal material and/or developmental needs ( Masters, 2010). 2010 ). One of the signature properties of a critical system is a maximal sensitivity sensitivity to perturbation perturbation (Bak, ( Bak, 19 1997 97;; Hesse and Gro Gross, ss, 20 201 14; Tagliazucchi et al., 2016a). 2016a). By this token, we may ask whether and how this translates to the psychedelic experience? The importance of set and setting to the the qual qualit ity y of a psyc psyche hede delictrip lictrip has has long long been been raised (Leary (Leary et al., 1963, 1963 , and see also Hartogsohn, 2016) 2016) and a recent perspective piece on the assumed importance of context , both to the quality of the acute psychedelic experience and subsequent sequent long-term long-term psychological psychological outcomes, has recently recently been published (Carhart-Harris (Carhart-Harris et al., 2018). 2018 ). Intriguingly, as discussed above, it seems that not all stimuli have added impact in the psychedelic state - but are dependent on being suf �ciently captivating and immersive for the individual (Kaelen (Kaelen et al., 2018). 2018 ). For example, in a recen recentt clinical clinical trial trial of psilocyb psilocybin in for depres depression sion,, music music played played to patients during the treatment session that was well liked and in resonance with their underlying emotional state was found to be strongly strongly associated with the occurrence of so-called so-called peak experi



‘

’

‘

‘

’

‘

7

of the concep conceptua tuall danger dangerss of supersuper-cri critica ticalit lity y raised raised above above howeve howeverr, namely (hypo)mania and so-called spiritual bypassing . Lastly, it is worth re�ecting whether enhanced criticality under psychedelics (Atasoy (Atasoy et al., 2017) 2017) may express in other functionally useful ways. As touched on earlier, the ability of psychedelics to relax prior assumptions may provide the necessary preconditions for the emergence of spontaneous insight. Conceptually, it seems reasonable to suppose that attunement of brain activity towards criticality may be a mechanism underlying spontaneous insight under psychedelics psychedelics (Atasoy et al., 201 2017 7). Avalanche-phenomena and/or cascading processes in responses to intrinsic perturbation are signatures of critical systems (Petermann ( Petermann et al., 2009) 2009 ) and may be involved in the disinhibition and associated release of previously ously inhibi inhibited ted inform informati ation on under under psyche psychedel delics ics (Alon Alonso so et al., 20 201 15; Carhart-Ha Carha rt-Harris rris et al., 201 2014 4; Kaelen et al., 2016). 2016 ). The collapse of functio functional nal hierar hierarchie chiess that that serve serve to mainta maintain in the staus staus quo mayalso be key, enabling freer communication between the different levels e such as between the evolutionarily older emotional circuitry of the brain (e.g. the limbic system) and the cortex, perhaps through periodic cascades propogating through the system (e.g. see Kaelen et al., 2016). 2016). These matters are speculative but deserving of discussion - if only to earmark them for the future when it is easier to formulate our hypotheses more clearly and test them accordingly. ‘

’

‘

’

The unconscious is a thing of nature. (Carl Jung)

“

”

’

’

‘

In all chaos chaos there there is cosmos, in all disorder disorder,, a secret secret order. order. (Carl Jung) “

”

8. Serotoni Serotonin n and the entropic brain

Before concluding this paper, it seems appropriate to link in recent advances in serotonin research to the entropic brain hypothesis. A particularly exciting development is the discovery that unlike the dopamine system (Schultz, ( Schultz, 201 2016 6), serotonin appears not to encode encode classic classic rewa reward/ rd/pun punishm ishment ent inform informati ation on but rather rather valuevaluenonspeci�c surprise (Matias ( Matias et al., 2017). 2017). More speci�cally, optogenetic techniques in mice have revealed that serotonin serotonin expressing neurons within the dorsal raphe nuclei �re in response to unexpected outcomes independent of their value sign (Matias ( Matias et al., 2017). 2017 ). This matter is particularly intriguing as averaged surprise is formally equivalent to uncertainty, and is therefore effectively synonymous with entropy (Bestmann ( Bestmann et al., 2008). 2008). Key questions then then ensue, ensue, why does does this this happen happen,, and what functio function n does does it ‘

’







8


through enhancing one's endurance of uncertainty through stressmoderation, rather than adaption to it through changes in outlook and behav behaviour iour ( Carha Carhart-Ha rt-Harris rris and Nutt, 201 2017 7). Mechanisticall Mechanistically, y, serotonin serotonin 2A receptor receptor signalling has been hypothesis hypothesised ed to serve a function analogous to annealing in metallurgy or system reset in computing (Carhar (Carhart-Har t-Harris ris and Nutt Nutt,, 201 2017 7; Carhart-Harris et al., 2017c)) where 2017c where throug through h enhance enhanced d excit excitabil ability ity,, the in�uence uence of prior beliefs is relaxed e as per a � attened energy landscape e so that new learning can occur. ‘

’

‘

’

considered retracted but rather rather side-st side-stepped epped for the time time being, being, in the intere interests sts of exped expedien iency cy.. It should should be clearl clearly y stated stated howeve howeverr, that that the position that psychedelic research offers a unique opportunity for major principles of psychoanalytic theory to be tested, veri �ed and revived is still very much maintained. There is a door ajar here for psychoanalyt psychoanalytically ically-mind -minded ed experimen experimental tal psychologists psychologists and neuroscientists to open and walk through. ‘

’

Until you make the unconscious conscious it will direct your life and you will call it fate. (Carl Jung)

“

”

Your assumptions are your window on the world, scrub them off every once in a while, or the light won't come in. (Isaac Asimov) “

”

9. Discussion Discussion

This article has revisited the so-called entropic brain hypothesis (Carhart-Harris et al., 2014). 2014 ). It has cited increasing empirical support for the idea since it was originally published in early 2014 (Carhart-Harris et al., 2014) 2014 ) and highlighted a particularly promising measure of brain entropy, Lempel-Ziv, that has proved to be informativ informative e about conscious level in disorders disorders of consciousness consciousness (Casali et al., 2013), 2013), pharmacologically induced loss of consciousness (Schartner (Schartner et al., 2015; 2015 ; Zhang et al., 2001) 2001) and psychedelicinduced consciousness enrichment (Schartner ( Schartner et al., 2017). 2017 ). It has attempted to tackle the question of what increased increased entropy in the brain relates to in terms of conscious experience, proposing that and subjective richness of conscious experience, information content and uncertainty are all close relatives - if not direct counterparts - of increased brain entropy (at least within a critical zone). Speci �c challenges for the entropic brain theory, and ideas about how it may be tested and advanced, were discussed. Two speci �c examples were provided of how the entropic brain might be clinically applied applied,, i.e. i.e. throug through h using using psyche psychedel delics ics to facilit facilitate ate emotio emotional nal insight and/or treat disorders of consciousness. The former may be likened to the use of free-association in psychoanalysis, where an open, free-�owing mindstate is encouraged so that the liklihood of spontan spontaneou eouss insight insight is enhanc enhanced. ed. Closing Closing section sectionss focused focused on properties of criticality in the brain and how these may be accentuated under psychedelics (Atasoy (Atasoy et al., 2017) 2017) as well as recent advances in serotonin research that chime well with the entropic brain and may be usefully combined with it to solve a major riddle in psychopharmacology, namely what is brain serotonin for ? The proposed solution being: to differentially encode behavioural re‘

’

These substances substances [psychedelic [psychedelics] s] function as unspeci�c amplithat increase the energetic niveau in the psyche and make the deep unconscious unconscious dynamics available for conscious processing. This unique property of psychedelics makes it possible to study psychological undercurrents that govern our experiences and behaviors to a depth that cannot be matched by any other methods and tools available in modern mainstream science. (Stanislav Grof) “

�ers

”

Brie�y, one speci�c hypothesis contained in the original paper (Carhart-Harris et al., 2014) 2014 ) that has not stood the test of time, can now be revised, namely that the brain during seizure is sub-critical in relation to normal waking consciousness; consciousness; in fact, evidence suggests it is super-critical (Meisel (Meisel et al., 2012) 2012) e which, with the bene�t of hindsight, hindsight, makes much more sense. About the speci�c limitations of the present paper, it has been selective in its focus, and unlike the original ( Carhart-Harris et al., 2014), 2014 ), has said little about other altered states of consciousness in which which entrop entropy y may may be eleva elevated ted above above the normal normal wakin waking g baseline. baseline. Be�ttin tting g its its rich richer er conte content nt and and emot emotion ional al tone tone,, it has has been been shown that REM sleep is more entropic entropic than NREM sleep (Abasolo et al., 2015; 2015; Burioka et al., 2005) 2005 ) but what about psychosis? The varieg variegate ated d nature nature of this this disorde disorderr means means we must must be cautious cautious about making too general and therefore therefore misleading statements statements about it. For example, we can speculate that whereas entropy/uncert certai aint nty/ y/con conte tent nt may may be elev elevat ated ed in mani manicc state statess (e.g (e.g.. see see Thomasson et al., 2002) 2002) and early and acute psychotic episodes, it may be suppressed once a � xed delusion has formed formed e and/or an antipsychotic antipsychotic and/or mood-stabili mood-stabilising sing medication medication is introduced introduced and becomes effective e for example see (M ( Mendez et al., 2012) 2012 ) for evidence of decreased brain entropy after treatment with mirtazapine for depression. Also, while the literature is replete with studies applying entropy/complexity measures to EEG data recorded in the context of 








Another limitation of the present paper is that although explicit mention has been given to the Lempel-Ziv measure ( Schartner et al., 2015), 2015), only general statements about it have been made for greater detail see (Schartner ( Schartner et al., 2015; 2015 ; Zhang et al., 2001). 2001). For example, perhaps there are reasons to focus on the compressibility of signals detected from speci�c spatial locations when studying speci�c subjective phenomena (e.g. occipital sensors and visual phenomena) or to improve the temporal precision of our sampling so as to more accurately accurately map between between neurophysiolo neurophysiological gical and phenomenological events or epochs e as discussed above. It is hoped that more nuanced hypotheses arising from the entropic brain theory can be tested in the future. Relatedly, brain entropy has been treated here as a global brain phenom phenomeno enon n but there there are are reasons reasons to be believ believe e that that spatial spatial localisation is relevant to both the action of psychedelics and the neurobiology neurobiology of consciousness. consciousness. For example, example, the serotonin serotonin 2A receptors that appear to be the key trigger receptors for the psychedelic experience (Nichols, (Nichols, 2016) 2016) have their densest expression in high-l high-leve evell cortica corticall region regionss belongi belonging ng to the defaul default-m t-mode ode network (Beliveau ( Beliveau et al. 2017) 2017) and this network, as well as other fronto-par fronto-parietal ietal networks, networks, have been closely closely implicated implicated in consciousness regulation (Guldenmund (Guldenmund et al., 2016) 2016) e as they have in the psychedelic psychedelic state (Tag Tagliazuc liazucchi chi et al., 201 2016b 6b;; Carhart-Harris et al., 2016b). 2016b). Anothe Anotherr key issue deserv deserving ing of focus focus before before closing, closing, is the matter of the relationship between entropy and criticality. It seems reasona reasonable ble to infer infer that that such a relati relationsh onship ip exists exists but nothin nothing g speci�c has yet been said about this. Is it more accurate to describe the psychedelic psychedelic brain as critical or dynamically dynamically instable instable than entropic ? Is there a limit to the rule that increased brain entropy relates relates to increased increased richness of conscious conscious content? content? The answer answer to this last question is probably yes , and more speci �cally, it seems likely that there is a zone of criticality ( Moretti and Munoz, 2013) 2013) above which any further increases in brain entropy create a state of mind and brain that is incapable of integrating information into coherent wholes (Gallimore, (Gallimore, 201 2015 5). Anecdotal reports of complete and/or near-compl near-complete ete loss of consciousness consciousness under psychedeli psychedelics cs can be foun found d (https://erowid.org/experiences/ https://erowid.org/experiences/)) but but are are rare rare.. Thus, Thus, generally generally speaking, the entropic entropic brain brain principle, principle, that increased brain entropy relates to an increased richness of conscious experience, may be said to stand, but only within an upper as well as a lower limit (Fig. (Fig. 1). 1). It is interesting to re �ect that identifying the point at which conscious awareness awareness is lost with psychedelics psychedelics may be informative about consciousness itself - in the same way that anaesthetic-induced loss of consciousness has been well used to ‘

‘

’

’

“

‘

’

‘

’

9

been said in a critique of the original entropic brain paper that entropy/c entropy/comple omplexity xity measures measures applied applied to brain function merely merely depurate the integratio integration n term from the integratedintegrated-inform information ation theory (Papo, (Papo, 2016). 2016). This charge is readily accepted but the position is taken here that the entropy/complexity component of the integr integrate ated-i d-infor nformat mation ion theory theory provide providess the major major share share of its explanatory power. This position is empirically substantiated, since it is arguably the complexity/entropy more than the integration measures per se that are so impressively predicting conscious level (Casali et al., 2013; 2013; Casarotto et al., 2016; 2016; Schartner et al., 2015; 2015 ; Zhang et al., 2001). 2001). While the requirement for integration is not disregarded disregarded (e.g. (e.g. see the discussion discussion on entropy entropy and criticality criticality in the previous paragraph) and may indeed by critical for access consciousness particularly e it is felt that the key properties of such integration, necessary for consciousness, have not yet been clearly deline delineate ated d - althou although gh see the Global Global Works Workspace pace theory theory ( Baars, 1993)) for an appealing model on the importance of integration to 1993 conscious experience, as well as more recent work on large-scale (Tag agli liaz azuc ucch chii et al al., ., 20 201 16a 6a)) and and long long-r -ran ange ge conne connect ctiv ivit ity y (Kotchoubey et al., 2013). 2013 ). It also remains possible that a role for integration may be implied within entropy/complexity measures; for example, future work may discover the point or zone within which which entr entrop opy y exce exceed edss a crit critica icall thre thresh shold old at whic which h no one one coherent, coherent, large-scale large-scale spatiotempor spatiotemporal al con�guration can dominate the brain for a suf �ciently long-enough for access consciousness to be possible. All models models are incomp incomplet lete e and the entrop entropic ic brain brain is no excep exceptio tion n - but it was conceived and intended to offer a simple and useful heuristic, enabling relatively seamless translations to be made between tween a quantitati quantitative ve measure of the richness of brain activity activity and the richness of subjective experience. ‘

’

”

10. Conclusions

In summary, four years on from the publication of the original entropic brain hypothesis, the present paper has sought to re �ect on its in�uence, reliability reliability and future future scienti scienti�c and clinical value. The positio position n is mainta maintaine ined d that that entrop entropy y repres represent entss a uniqu uniquely ely powerful bridging tool for human neuroscience that will enable a better better underst understand anding ing of the mind-b mind-brai rain n relati relationsh onship ip and mechan chanics ics of consc consciou iousne sness, ss, incl includi uding ng how how we may may trea treatt its its abnormalities.







10


Appendix A. Supplementary data

Supple Supplemen mentar tary y data data relat related ed to this this article article can be found found at https://doi.org/10.1016/j.neuropharm.2018.03.010 . References Abasolo, D., Simons, S., Morgado da Silva, R., Tononi, G., Vyazovskiy, V.V., 2015. Lempel-Z Lemp el-Ziv iv comp complex lexity ity of cort cortical ical acti activity vity during slee sleep p and wak waking ing in rats rats.. J. Neuroph Neurophysiol. ysiol. 113, 113, 2742e2752 2752.. Akdemir Akar, S., Kara, S., Agambayev, S., Bilgiç, V., 2015 Dec 1. Nonlinear analysis of EEGs EEGs of patients patients with major major depressio depression n during during different different emotional emotional states. states. Comput Biol. Med. 67, 49e60. https://doi.org/10.1016/ j.compbiomed.201 j.compbiome d.2015.09.01 5.09.019 9. Alonso, J.F., Romero, S., Mananas, M.A., Riba, J., 2015. Serotonergic psychedelics psychedelics tempo te mporar rarily ily mo modif dify y inf inform ormati ation on tra transf nsfer er in hum humans ans.. Int Int.. J. Neu Neuro ro-psychopharmacol. 18. 18. Atasoy, S., Roseman, L., Kaelen, M., Kringelbach, M.L., Deco, G., Carhart-Harris, R.L., 2017. 201 7. Connectome-harmonic Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD. Sci. Rep. 7, 17661 . Baars,, B.J., 1993. Baars 1993. How does a seri serial, al, inte integra grated ted and very limited limited stre stream am of consciousness emerge from a nervous system that is mostly unconscious, distributed, parallel and of enormous capacity? Ciba Found. Symp. 17 174, 4, 291e303, 282290; discussion. discussion. Bak, P., 1997. How Nature Works : the Science of Self-organized Criticality. Oxford University Press, Oxford. Oxford . Barrett, F.S., Preller, K.H., Herdener, M., Janata, P., Vollenweider, F.X., 2017. Serotonin 2A receptor signaling underlies LSD-induced alteration of the neural response to dynamic changes in music. Cerebr. Cortex 1 e12 12.. Barttfeld, P., Uhrig, L., Sitt, J.D., Sigman, M., Jarraya, B., Dehaene, S., 2015. Signature of consciousness in the dynamics of resting-state brain activity. Proc. Natl. Acad. Sci. U. S. A. 112, 887 e892 892.. Basar,, E., Gunt Basar Guntekin ekin,, B., 2009. Darw Darwin's in's evolution evolution theo theory, ry, brain osci oscillat llations, ions, and complex brain function in a new " Cartesian view". Int. J. Psychophysiol. 71, 2e8. Bedi, G., Cecchi, G.A., Slezak, D.F., Carrillo, F., Sigman, M., de Wit, H., 2014. A window into the intoxicated mind? Speech as an index of psychoactive drug effects. Neuropsychopharma Neuropsy chopharmacology cology 39, 2340e2348 2348.. Bedi, G., Carrillo, F., Cecchi, G.A., Slezak, D.F., Sigman, M., Mota, N.B., Ribeiro, S., Javitt, D.C., Copelli, M., Corcoran, C.M., 2015 2015.. Automated analysis of free speech predicts psychosis onset in high-risk youths. NPJ Schizophr 1, 15030. 15030 . Beliveau, V., Ganz, M., Feng, L., Ozenne, B., H ø jgaard, L., Fisher Fisher,, P. P.M., M., Svarer Svarer,, C., Greve, D.N., Knudsen, G.M., 2017. A high-resolution in vivo atlas of the human Brain's serotonin system. J. Neurosci. 37 (1), 120 e128 128.. Ben-Naim BenNaim,, A., 2007 2007.. Entr Entropy opy Dem Demysti ysti�ed : th the e Se Secon cond d Law Reduce Reduced d to Pla Plain in Common Sense. World Scienti �c, Hackensack, N.J. N.J. Bestmann, S., Harrison, L.M., Blankenburg, F., Mars, R.B., Haggard, P., Friston, K.J., Rothwell, J.C., 2008. In�uence of uncertainty and surprise on human corticospinal excitability during preparation for action. Curr. Biol. 18, 775 e780 780.. Block, N., 2005 Feb. Two neural correlates correlates of consciousness. Trends Cognit. Sci. 9 (2), 46e52 52.. Bogenschutz, M.P., Johnson, M.W., 2016. Classic hallucinogens in the treatment of addictions. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 64, 250 e258 258.. Bouso,, J.C., Palh Bouso Palhanoano-Font Fontes, es, F. F.,, Rodr Rodrigue iguez-Fo z-Fornel rnells, ls, A., Ribe Ribeiro, iro, S., Sanc Sanches, hes, R., Crippa, J.A., Hallak, J.E., de Araujo, D.B., Riba, J., 2015. Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans. Eur. Neuropsychopharmacol 25, 483 e492 492..

Psychiatry 3, 619e627 627.. Carhart-Harris, R.L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, Murph y, K., Ta Taglia gliazucch zucchi, i, E., Schenberg, Schenberg, E.E., Nest Nest,, T., Orban, C., Leec Leech, h, R., Williams, L.T., Williams, T.M., Bolstridge, Bolstridge, M., Sessa, B., McGonigle, J., Sereno, M.I., Nichols, D., Hellyer, P.J., Hobden, P., Evans, J., Singh, K.D., Wise, R.G., Curran, H.V., Feilding, A., Nutt, D.J., 2016b. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc. Natl. Acad. Sci. U. S. A. 113, 4853 e4858 4858.. Carhart-Harris, R.L., Bolstridge, M., Day, C.M.J., Rucker, J., Watts, R., Erritzoe, D.E., Kaelen, Kael en, M., Giribaldi, Giribaldi, B., Bloo Bloom m �eld, M., Pill Pilling, ing, S., Ricka Rickard, rd, J.A., Forb Forbes, es, B., Feilding, A., Taylor, D., Curran, H.V., Nutt, D.J., 2017a. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology chopharmaco logy (Berlin) (Berlin).. Carhart-Harris, R.L., Erritzoe, D., Haijen, E., Kaelen, M., Watts, R., 2017b. Psychedelics and connected connectedness. ness. Psychoph Psychopharmacology armacology (Berlin). (Berlin) . CarhartCarh art-Harr Harris, is, R.L. R.L.,, Rose Roseman, man, L., Bolst Bolstridg ridge, e, M., Deme Demetrio triou, u, L., Pann Pannekoe ekoek, k, J.N., Wall, Wal l, M.B. M.B.,, Ta Tanner nner,, M., Kael Kaelen, en, M., McGo McGonigl nigle, e, J., Murph Murphy, y, K., Leec Leech, h, R., Curran, H.V., Nutt, D.J., 2017c. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci. Rep. 7, 13187. 13187. Carhart-Harris, Carhart-Harris, R.,L., Roseman, L., Haijen, E., Erritzoe, D.E., Watts, R., Branchi, I., Kaelen, Kaelen, M., 2018. 2018. Psyched Psychedelic elicss and the essentia essentiall importan importance ce of context context.. J. Psychopharmacol. Psychopharmacol. https://doi. org/10.1 org/10.1177/02698811 177/026988111875471 18754710 0. Carrillo, F., Sigman, M., Fern andez Slezak, D., Ashton, P., Fitzgerald, L., Stroud, J., Nutt, Nutt, D.J., CarhartCarhart-Harr Harris, is, R.L., 2018. Natural Natural speech speech algorith algorithm m applied applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant treatment-resistant depression. J. Affect. Disord. 230, 84 e86. 86. https://doi.org/ 10.1016/j.jad.2018.01.006,, 2018 Apr 1. 10.1016/j.jad.2018.01.006 Carter,, O.L., Burr, D.C., Pettigre Carter Pettigrew, w, J.D., Wallis, G.M., Hasler Hasler,, F., Vollenweider, Vollenweider, F.X., 2005. Usin Using g psilo psilocybi cybin n to inve investig stigate ate the rela relation tionship ship betw between een atte attentio ntion, n, working memory, memory, and the serotonin 1A and 2A receptors. J. Cognit. Neurosci. 17 17,, 1497e1508 1508.. Casali Cas ali,, A.G A.G.,., Go Gosse sserie ries, s, O., Ro Rosan sanov ova, a, M., Bol Boly y, M., Sar Sarass asso, o, S., Cas Casali ali,, K.R K.R.,., Casarott Casar otto, o, S., Brun Bruno, o, M.-A M.-A.,., Laur Laureys, eys, S., To Tononi noni,, G., Massi Massimini mini,, M., 201 2013a. 3a. A theoretically based index of consciousness independent of sensory processing and behavior. Sci. Transl. Med. 5, 198 ra105. ra105 . Casarotto, S., Comanducci, A., Rosanova, M., Sarasso, S., Fecchio, M., Napolitani, M., Pigorini, A.,A.,G.C., Trimarchi, P.D., Boly, M., Gosseries, O., Bodart, O., Curto, F., Landi, C., Mariotti, M., Devalle, G., Laureys, S., Tononi, G., Massimini, M., 2016. Strati �cation of unresponsive patients by an independently validated index of brain complexity. Ann. Neurol. 80, 718 e729 729.. Christoff, K., Gordon, A.M., Smallwood, J., Smith, R., Schooler, J.W., 2009. Experience sampling during fMRI reveals default network and executive system contributions to mind wandering. Proc. Natl. Acad. Sci. U. S. A. 106, 8719 e8724 8724.. Cohen, S., 1964. The beyond within; the LSD Story, by Sidney Cohen. Foreword by Gardner Murphy. Atheneum, New York. York . Cohen, J.D., McClure, S.M., Yu, A.J., 2007. Should I stay or should I go? How the human huma n brai brain n mana manages ges the trad trade-of e-offf betw between een expl exploita oitation tion and expl explorat oration. ion. Philos. Trans. R. Soc. Lond. B Biol. Sci. 362, 933 e942 942.. Deco, G., Kringelbach, M.L., 2017. 2017. Hierarchy of information processing in the brain: a novel 'intrinsic ignition' framework. Neuron 94, 961 e968 968.. Deco,, G., Tagliazucc Deco Tagliazucchi, hi, E., Laufs, H., Sanj Sanju u an, A., Kringelbac Kringelbach, h, M.L., 201 2017. 7. Novel intrinsic ignition method measuring local-global integra integration tion characterizes wakefulness and deep sleep. Eneuro 4 (5). ENEURO-0106 . Edwards, Edw ards, C.L., Ruby Ruby,, P.M., Malin Malinows owski, ki, J.E. J.E.,, Benn Bennett ett,, P.D., Blag Blagrov rove, e, M.T M.T.,., 201 2013. 3. Dreaming and insight. Front. Psychol. 4, 979 . Ellam Ell amil, il, M., Fo Fox, x, K.C K.C.,., Dix Dixon on,, M.L M.L.,., Pr Pritc itchar hard, d, S., To Todd, dd, R.M R.M.,., Tho Thomps mpson, on, E., Christoff, K., 2016. Dynamics of neural recruitment surrounding the spontaneous arising of thoughts in experienced mindfulness practitioners. Neuroimage 136, 186e196 196.. 










Deco, G., Guldenmund, P., Vanhaudenhuyse, A., Boly, M., Laureys, S., Soddu, A., 2012. A default mode of brain function in altered states of consciousness. Arch. Ital. Biol. 150 (2e3), 107e121 121.. Harman, W.W., McKim, R.H., Mogar, R.E., Fadiman, J., Stolaroff, M.J., 1966. Psychedelicc agen deli agents ts in crea creativ tive e prob problemlem-solv solving: ing: a pilo pilott study study.. Psy Psychol chol.. Rep Rep.. 19 19,, 211 21 1e227 227.. Hartogsohn, I., 2016. Set and setting, psychedelics and the placebo response: an ext xtra ra-p -pha harm rmac acol olog ogic ical al pers pe rspe pect ctiv ive e on psy ps ych chop opha harm rmac acol olog ogy y. J. Psychoph Psychopharmacol. armacol. 30, 1259 e1267 1267.. Hesse, J., Gross, T., 2014. Self-organized criticality as a fundamental property of neural systems. Front. Syst. Neurosci. 8, 166 . Huxley, A., 1959. The Doors of Perception and Heaven and Hell. Penguin Books, Harmondsworth . Huxley, A., Palmer, C., Horowitz, M., 1977. Moksha : Writings on Psychedelics and the Visionary Experience (1931-1963). (1931-1963). Stonehill, New York. York . Janiger,, O., Derios, M.D., 1989. Lsd and creativity. J. Psychoac Janiger Psychoact. t. Drugs 21, 129e134 134.. Kaelen, Kael en, M., Rose Roseman, man, L., Kaha Kahan, n, J., Sant Santos-Ri os-Ribeir beiro, o, A., Orban, C., Lorenz, R., Barrett, F.S., Bolstridge, M., Williams, T., Williams, L., Wall, M.B., Feilding, A., Muthukumaraswamy Muthukumaras wamy,, S., Nutt, D.J., Carhart-Harris, R., 201 2016. 6. LSD modulates music-induced imagery via changes in parahippocam parahippocampal pal connectivity. Eur. Neuropsychopharmacol . Kaelen, M., Giribaldi, B., Raine, J., Evans, L., Timmerman-Slater, C., Rodriguez, N., Roseman, L., Feilding, A., Nutt, D., Carhart-Harris, Carhart-Harris, R., 2018. 2018. The hidden therapist: eviden evidence ce for a centr central al role role of music music in psyche psychedel delic ic thera therapy py.. Psycho Psycho-phramrc phramrcolog ology y (Springe (Springer) r) 235 (2), 505e519. https://doi.org/10.1007/s00213017-4820-5.. 017-4820-5 Klonowski, W., Jernajczyk, W., Niedzielska, K., Rydz, A., Stepien, R., 1999. Quantitative measure of complexity of EEG signal dynamics. Acta Neurobiol. Exp. 59, 315e321 321.. Kotchoubey, B., Merz, S., Lang, S., Markl, A., Müller, F., Yu, T., Schwarzbauer, C., 2013. Global functional connectivity reveals highly signi �cant differences between the vegetative and the minimally conscious state. J. Neurol. 260 (4), 975 e983 983.. Kraehenmann, R., Preller, K.H., Scheidegger, M., Pokorny, T., Bosch, O.G., Seifritz, E., Vollenweider Vollen weider,, F.X., 2015. Psilocybin-induced decrease in amygd amygdala ala reactiv reactivity ity correlates with enhanced positive mood in healthy volunteers. Biol. Psychiatr. 78, 572e581 581.. Kraehenmann, R., Schmidt, A., Friston, K., Preller, K.H., Seifritz, E., Vollenweider, F.X., 2016. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. Neuroimage Clin 11, 53 e60 60.. Kraehenmann, Kraehenm ann, R., Pokorn Pokorny, y, D., Aicher Aicher,, H., Preller Preller,, K.H., Pokorny Pokorny,, T., Bosch, O.G., Seifritz, E., Vollen Vollenweider weider,, F.X., 2017. 2017. LSD increases primary process thinking via serotonin 2A receptor activation. Front. Pharmacol. 8, 814 . Kraehenmann, R., Pokorny, D., Vollenweider, L., Preller, K.H., Pokorny, T., Seifritz, E., Vollenweider, F.X., 2017. 2017. Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation. Psychopharmacology (Berlin) 13, 2031e2046. https://doi.org/10.1007/s00213-017-4610-0 2046. https://doi.org/10.1007/s00213-017-4610-0.. Kuypers Kuy pers,, K.P K.P.,., Riba, J., de la Fuen Fuente te Revenga, Revenga, M., Bark Barker er,, S., Theunissen, Theunissen, E.L., Ramaekers, J.G., 2016. Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking. Psychoph Psychopharmacology armacology (Berlin) 233, 3395e3403 3403.. Leary, T., Litwin, G.H., Metzner, R., 1963. Reactions to psilocybin administered in a supportive environment. J. Nerv. Ment. Dis. 137, 561 e573 573.. Lebedev, A.V., Lovden, M., Rosenthal, G., Feilding, A., Nutt, D.J., Carhart-Harris, R.L., 2015. Finding the self by losing the self: neural correlates of ego-dissolution under psilocybin. Hum. Brain Mapp. 36, 3137e3153 3153.. Lebedev, A.V., Kaelen, M., Lovden, M., Nilsson, J., Feilding, A., Nutt, D.J., CarhartHarris, Harr is, R.L. R.L.,, 201 2016. 6. LSD-i LSD-induc nduced ed entr entropic opic brain activity activity pred predicts icts subse subseque quent nt personality change. Hum. Brain Mapp.

11

Mende ndez, z, M.A M.A.,., Zul Zuluag uaga, a, P., Ho Horne rnero, ro, R., G omez, C., Escud Escudero ero,, J., Rod Rodrígu ríguezezPalancas, A., Ortiz, T., Fern andez, A., 2012. Complexity analysis of spontaneous brain bra in act activi ivity ty:: eff effec ects ts of dep depre ressi ssion on and ant antide idepre pressa ssant nt tre treatm atmen ent. t. J. Psychoph Psychopharmacol. armacol. 26 (5), 636 e643 643.. Milliere, R., 2017. Looking for the self: phenomenology, neurophysiology and philosophical signi�cance of drug-induced ego dissolution. Front. Hum. Neurosci. 11, 245. 245. Moreno, F.A., Wiegand, C.B., Taitano, E.K., Delgado, P.L., 2006. Safety, tolerability, and ef �cacy of psilocybin in 9 patients with obsessive-compulsive disorder. J. Clin. Psychiatr. 67, 1735e1740 1740.. Moretti, P., Munoz, M.A., 2013. Grif �ths phases and the stretching of criticality in brain networks. Nat. Commun. 4, 2521. 2521. Mueller,, F., Lenz, C., Dolder, P.C., Harder, Mueller Harder, S., Schmid, Y., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl. Psychiatry 7, e1084 . Muller, F., Lenz, C., Dolder, P., Lang, U., Schmidt, A., Liechti, M., Borgwardt, S., 2017. Increased thalamic resting-state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr. Scand. 136, 648 e657 657.. Muthuk Mut hukuma umara rasw swam amy, y, S.D S.D.,., Car Carhar hartt-Har Harris ris,, R.L R.L.,., Mor Moran, an, R.J R.J.,., Bro Brook okes, es, M.J M.J.,., Williams, Will iams, T.M., Errt Errtizoe izoe,, D., Sess Sessa, a, B., Papa Papadopo dopoulos, ulos, A., Bols Bolstrid tridge, ge, M., Singh, Sing h, K.D. K.D.,, Feil Feilding ding,, A., Fri Friston ston,, K.J. K.J.,, Nutt Nutt,, D.J. D.J.,, 201 2013. 3. Broa Broadban dband d cort cortical ical desynchr desy nchroni onizati zation on unde underlie rliess the huma human n psyc psychede hedelic lic stat state. e. J. Neur Neurosci osci.. 33, 15171e15183 15183.. Muzio, J.N., Roffwarg, H.P., Kaufman, E., 1966. Alterations in the nocturnal sleep cycle resulting from LSD. Electroencephalogr. Clin. Neurophysiol. 21, 313 e324 324.. Nakai, T., Bagarinao, E., Matsuo, K., Ohgami, Y., Kato, C., 2006. Dynamic monitoring of brain activation under visual stimulation using fMRI ethe advantage of realtime fMRI with sliding window GLM analysis. J. Neurosci. Meth. 157, 158 e167 167.. Nandrino Nand rino,, J.L. J.L.,, Peza Pezard, rd, L., Mart Martiner inerie, ie, J., el Massi Massioui, oui, F., Ren Renault ault,, B., Jouve Jouvent, nt, R., Allilaire, J.F., Widlocher, D., 1994. Decrease of complexity in EEG as a symptom of depression. Neuroreport 5, 528 e530 530.. Naselaris, T., Prenger, R.J., Kay, K.N., Oliver, M., Gallant, J.L., 2009. Bayesian reconstruction of natural images from human brain activity. Neuron 63, 902 e915 915.. Nichols, D.E., 2016. Psychedelics. Pharmacol. Rev. 68, 264 e355 355.. Nutt, D.J., King, L.A., Nichols, D.E., 2013. Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nat. Rev. Neurosci. 14, 577 e585 585.. Olofsen, E., Sleigh, J.W., Dahan, A., 2008. Permutation entropy of the electroencephalogram: cephalogr am: a measure of anaesthetic drug effect. Br. J. Anaesth.101 Anaesth.101,, 810 e821 821.. Palhano-Fontes, Palhano-F ontes, F., Andrade, K.C., Tofoli, L.F., Santos, A.C., Crippa, J.A.S., Hallak, J.E.C., Ribeiro, S., de Araujo, D.B., 2015. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS One 10, e0118143. e0118143. Papo,, D., 201 Papo 2016. 6. Comm Commenta entary: ry: the entr entropic opic brain: a theo theory ry of cons consciou ciouss stat states es informed infor med by neur neuroima oimaging ging rese researc arch h with psyc psyched hedelic elic drug drugs. s. Fro Front. nt. Hum. Neurosci. 10, 423. 423. Peterma Pet ermann, nn, T., Thia Thiagara garajan, jan, T.C T.C.,., Lebe Lebedev dev,, M.A. M.A.,, Nico Nicoleli lelis, s, M.A. M.A.,, Chial Chialvo, vo, D.R. D.R.,, Plenz, D., 2009. Spontaneous cortical activity in awake monkeys composed of neuronal avalanches. Proc. Natl. Acad. Sci. U. S. A. 106, 15921 e15926 15926.. Petitme Pet itmengin ngin,, C., 201 2017 7. Enac Enaction tion as a liv lived ed exp experie erience nce tow towards ards a radi radical cal neur neuroophenomenology. phenomeno logy. Constructivist Foundations 12, 139 e14 147 7. Petri, Pet ri, G., Expe Expert, rt, P., Turk Turkheim heimer er,, F. F.,, Carh Carhartart-Harr Harris, is, R., Nutt Nutt,, D., Hell Hellyer yer,, P.J., Vaccarino, F., F., 2014. Homological scaffolds of brain functional networks. J. R. Soc. Interface 11, 20140873. 20140873. Pezard, L., Nandrino, J.L., Renault, B., ElMassioui, F., Allilaire, J.F., J.F., Muller, J., Varela, F.J., Martiner Mart inerie, ie, J., 1996. Depression Depression as a dyna dynamica micall dise disease. ase. Biol Biol.. Psy Psychia chiatr tr.. 39, 991e999 999.. Preller Pre ller,, K.H. K.H.,, Poko Pokorny rny,, T., Hock Hock,, A., Krae Kraehenm henmann, ann, R., Sta Stamp mp �i, P., Seifr Seifritz, itz, E., Scheidegger, M., Vollenweider, F.X., 2016. Effects of serotonin 2A/1A receptor 













12


Sampedro, F., de la Fuente Revenga, M., Valle, M., Roberto, N., Dominguez-Clave, E., Elices, M., Luna, L.E., Crippa, J.A.S., Hallak, J.E.C., de Araujo, D.B., Friedlander, P., Barker,, S.A., Alvarez Barker Alvarez,, E., Soler Soler,, J., Pascual, J.C., Feilding, A., Riba, J., 201 2017. 7. Assessing the psychedeli psychedelicc "After-Glow " in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities. Int. J. Neuropsychopharmacol. 20, 698 e71 711 1. Sanches, R.F., de Lima Osorio, F., Dos Santos, R.G., Macedo, L.R., Maia-de-Oliveira, J.P., Wichert-Ana, L., de Araujo, D.B., Riba, J., Crippa, J.A., Hallak, J.E., 2016. Antidepressant pres sant effects of a sing single le dose of ayah ayahuasca uasca in patie patients nts with recu recurre rrent nt depression: a SPECT study. J. Clin. Psychopharmacol. 36, 77 e81 81.. Sandison, R.A., 1954. Psychological aspects of the LSD treatment of the neuroses. J. Ment. Sci. 100, 508e51 515 5. Schartner, M., Seth, A., Noirhomme, Q., Boly, M., Bruno, M.A., Laureys, S., Barrett, A., 2015. 201 5. Complexi Complexity ty of multi-dime multi-dimensional nsional spontaneous EEG decreases during propofol induced general anaesthesia. PLoS One 10, e0133532 . Scha Sc hart rtne nerr, M.M. M. M.,, Carh Ca rhar artt-Ha Harr rris is,, R.L. R. L.,, Barr Ba rret ett, t, A.B. A. B.,, Seth Se th,, A.K. A. K.,, Muthukumaraswamy, S.D., 2017. Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin. Sci. Rep. 7, 46421. 46421 . Sche Sc henb nber erg, g, E. E.E. E.,, Al Alex exan andr dre, e, J. J.FF.M .M., ., Fi File lev v, R. R.,, Cr Crav avo, o, A. A.M. M.,, Sa Sato to,, J. J.R. R.,, Muthukum Muth ukumaras araswam wamy, y, S.D. S.D.,, Yo Yonami namine, ne, M., Wa Wagues guespack, pack, M., Lomn Lomnicka, icka, I., Barker,, S.A., da Silveira, D.X., 2015. Acute biphasic effects of ayahuasca. PLoS One Barker 10, e0137202. e0137202. Schmidt, Schm idt, A., Mulle Muller, r, F., Lenz Lenz,, C., Dolder, Dolder, P.C., Schmid, Y., Zanchi, D., Lang Lang,, U.E U.E.,., Liechti, Liec hti, M.E., Borg Borgwar wardt, dt, S., 201 2017. 7. Acute LSD effe effects cts on resp response onse inhibition inhibition neural networks. Psychol. Med. 1 e13 13.. Schultz, W., 2016. Dopamine reward prediction error coding. Dialogues Clin. Neurosci. 18, 23e32 32.. Seth, A.K., Barrett, A.B., Barnett, L., 2011. Causal density and integrated information as me measu asures res of con consci scious ous le level vel.. Ph Philo iloss Tr Trans ans A Mat Math h Ph Phys ys Eng Sci 369 369,, 3748e3767 3767.. Shannon, C.E., 1949. The Mathematical Theory of Communication. The University of Illinois Press. Press. Shew,, W. Shew W.L., L., Plen Plenz, z, D., 201 2013. 3. The func function tional al bene�ts of crit critical icality ity in the cortex. cortex. Neuroscientist 19, 88e100 100.. Speth, J., Speth, C., Kaelen, M., Schloerscheidt, A.M., Feilding, A., Nutt, D.J., CarhartHarris, Harr is, R.L. R.L.,, 201 2016. 6. Decr Decrease eased d ment mental al time travel travel to the past correlates correlates with default-m defau lt-mode ode netw network ork disin disinteg tegrati ration on unde underr lys lysergi ergicc acid diet diethyl hylamid amide. e. J. Psychopha Psychopharmacol. rmacol. 30, 344e353 353.. Sun, L., Wang, Y.F., He, H., Chen, J., 2007. Changes of the alpha competitive structure after administration of single dose methylphenidate in different subtypes of attention attentio n de�cit hyperactivity hyperactivity disorder boys. Beijing Da Xue Xue Bao Yi Xue Ban 39 (3), 289e292 292.. Tagliazucchi, Tagliaz ucchi, E., 2017. 2017. The signatures of conscious access and its phenomen phenomenology ology are

Bonhomme, V., Noirhomme, Q., Laufs, H., Laureys, S., 2016a. Large-scale signatures of unconsciousness are consistent with a departure from critical dynamics. J. R. Soc. Interface 13, 20151027. 20151027. Tagliaz Tag liazucchi ucchi,, E., Rose Roseman, man, L., Kael Kaelen, en, M., Orba Orban, n, C., Muth Muthukum ukumaras araswam wamy, y, S.D. S.D.,, Murphy, Murph y, K., Laufs Laufs,, H., Leech, R., McGo McGonigl nigle, e, J., Cros Crossley sley,, N., Bullmore, Bullmore, E., Williams, T., Bolstridge, M., Feilding Feilding,, A., Nutt, D.J., Carhart-Harris, R., 2016b. Increased Incre ased glob global al funct functiona ionall conn connecti ectivity vity corr correlat elates es with LSD-i LSD-induce nduced d ego dissolution. Curr. Biol. 26, 1043 e1050 1050.. Thomasson, N., Pezard, L., 1999. Dynamical systems and depression: a framework for theoretical perspectives. Acta Biotheor. 47, 209 e21 218 8. Thomasson, N., Pezard, L., Allilaire, J.-F., Renault, B.M., Martinerie, Martinerie, J., 2000. Nonlinear EEG chan changes ges asso associat ciated ed with clin clinical ical impr improve ovemen mentt in depr depresse essed d patie patients. nts. Nonlinear Dynam. Psychol. Life Sci. 4, 203 e21 218 8. Thomasson, N., Pezard, L., Boyer, P., P., et al., 2002. Nonlinear EEG changes in a 48-hour cyclic manic-depressive patient. Nonlinear Dynam. Psychol. Life Sci. 6, 259 . Timmermann, C., Spriggs, M.J., Kaelen, M., Leech, R., Nutt, D.J., Moran, R.J., CarhartHarris, R.L., Muthukumaraswamy, S.D., 2017. LSD modulates effective connectivity tivi ty and neur neural al adapt adaptatio ation n mec mechani hanisms sms in an audit auditory ory oddball para paradigm digm.. Neuropharmacology . Timmermann, C., Roseman, L., Williams, L., Schartner, M., Leech, R., Feilding, A., Nutt, D.J., Carhart-Harris, R.L., 2018. Enter the Void: EEG Correlates of the DMT Experience(. In prep). prep). Tononi To noni,, G., Edel Edelman, man, G.M. G.M.,, 199 1998. 8. Cons Conscious ciousness ness and comp complexi lexity ty.. Scie Science nce 282, 1846e1851 1851.. Tononi To noni,, G., Spor Sporns, ns, O., Edel Edelman, man, G.M., 1994. A meas measure ure for brai brain n comp complex lexity: ity: relating functional segregation and integration in the nervous system. Proc. Natl. Acad. Sci. U. S. A. 91, 5033 e5037 5037.. Tononi, G., Boly, M., Massimini, M., Koch, C., 2016. Integrated information theory: from consciousness to its physical substrate. Nat. Rev. Neurosci. 17, 450 e461 461.. Torda, C., 1968. Contribution to serotonin theory of dreaming (LSD infusion). N. Y. State J. Med. 68, 1135 e1138 1138.. Valle, Vall e, M., Maq Maqueda, ueda, A.E., Rabel Rabella, la, M., Rod Rodrigu riguez-P ez-Pujada ujadas, s, A., Ant Antoni onijoan joan,, R.M. R.M.,, Romero, S., Alonso, J.F., Mananas, M.A., Barker, S., Friedlander, P., Feilding, A., Riba, J., 2016a. Inhibition of alpha oscillations through serotonin-2A receptor activatio activ ation n under underlies lies the visua visuall effec effects ts of aya ayahuasc huasca a in huma humans. ns. Eur Eur.. Neur Neuroopsychopharmaco. psychopharm aco. J . Eur. Coll. Neuropsyc Neuropsychopharmaco hopharmacol. l. 26, 1161 1161 e1175 1175.. Valle, Vall e, M., Maq Maqueda, ueda, A.E., Rabel Rabella, la, M., Rod Rodrigu riguez-P ez-Pujada ujadas, s, A., Ant Antoni onijoan joan,, R.M. R.M.,, Romero, S., Alonso, J.F., Mananas, M.A., Barker, S., Friedlander, P., Feilding, A., Riba, J., 2016b. Inhibition of alpha oscillations through serotonin-2A receptor activatio activ ation n under underlies lies the visua visuall effec effects ts of aya ayahuasc huasca a in huma humans. ns. Eur Eur.. Neur Neuroopsychopharmacol 26, 1161e1175 1175.. Varela, F., 1996. 1996. Neurophe Neurophenomenolog nomenology: y: a methodolo methodological gical remedy for the hard problem. J. Conscious. Stud. 3, 330 349

The Entropic Brain - Revisited

Recommend Documents